Ionizing radiation is useful in the treatment of cancer and for ablation of pathologic tissues because of the cytotoxic effects which result from persistent DNA double strand breaks or activation of program cell death (Haimovitz-Friedman et al., 1994; Garcia-Barros et al., 2003; Brown & Attardi, 2005). Radiation causes rapidly proliferating cells, such as tumor and cancer cells, to undergo cell death by apoptosis, both in vivo and in vitro (Antonakopoulos et al., 1994; Li et al., 1994; Mesner et al., 1997).
Current radiation therapy is frequently unsuccessful at completely eradicating cancer cells from a patient, however. This is true for at least two reasons. One reason cancer can recur is that it is often not possible to deliver a sufficiently high dose of local radiation to kill tumor cells without concurrently creating an unacceptably high risk of damage to the surrounding normal tissue. Another reason is that tumors show widely varying susceptibilities to radiation-induced cell death. Ionizing radiation activates pro-survival response through phosphoinositide 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase (MAPK) signal transduction pathways (Dent et al., 2003; Tan & Hallahan, 2003; Tan et al., 2006; Yacoub et al., 2006). PI3K catalyzes the addition of a phosphate group to the inositol ring of phosphoinositides normally present in the plasma membrane of cells (Wymann & Pirola, 1998). The products of these reactions, including phosphatidyl-4,5-bisphosphate and phosphatidyl-3,4,5-trisphosphate, are potent second messengers of several RTK signals (Cantley, 2002). In vitro studies have indicated that PI3K and Akt are involved in growth factor-mediated survival of various cell types (Datta et al., 1999), including neuronal cells (Yao & Cooper, 1995; Dudek et al., 1997; Weiner & Chun, 1999), fibroblasts (Kauffmann-Zeh et al., 1997; Fang et al., 2000), and certain cells of hematopoietic origin (Katoh et al., 1995; Kelley et al., 1999; Somervaille et al., 2001).
Another obstacle to designing effective radiotherapy is that there is a poor correlation between cellular responses to ionizing radiation in vitro and in vivo. For example, glioblastoma multiforme (GBM) is insensitive to radiation treatment, and has a universally fatal clinical outcome in both children and adults (Walker et al., 1980; Wallner et al., 1989; Packer, 1999). In vitro studies, however, show that human GBM cell lines exhibit radiosensitivity that is similar to that seen in cell lines derived from more curable human tumors (Allam et al., 1993; Taghian et al., 1993). In accord with the clinical data, the use of in vivo animal models has shown that GBM tumors in vivo are much more radioresistant than the cell lines used to produce them are in vitro (Baumann et al., 1992; Allam et al., 1993; Taghian et al., 1993; Advani et al., 1998; Staba et al., 1998). Thus, the inability to predict the radiosensitivity of a tumor in vivo based upon in vitro experimentation continues to be a significant obstruction to the successful design of radiotherapy treatments of human cancers.
Tumor cells could show enhanced radiosensitivity in vitro compared to in vivo due to the absence of an angiogenic support network in vitro, the presence of which appears to contribute to a tumor's radioresistance in vivo. The response of tumor microvasculature to radiation is dependent upon the dose and time interval after treatment (Kallman et al., 1972; Song et al., 1972; Hilmas & Gillette, 1975; Johnson, 1976; Yamaura et al., 1976; Ting et al., 1991). Tumor blood flow decreases when high doses of radiation in the range of 20 Grays (Gy) to 45 Gy are used (Song et al., 1972). In contrast, blood flow increases when relatively low radiation doses, for example below 500 rads, are administered (Kallman et al., 1972; Hilmas & Gillette, 1975; Johnson, 1976; Yamaura et al., 1976; Gorski et al., 1999). In irradiated mouse sarcomas, for example, blood flow increased during the 3 to 7 days immediately following irradiation (Kallman et al., 1972). Thus, the microvasculature might serve to protect tumor cells from radiation-induced cell death.
Thus, there exists an ongoing and long-felt need in the art for effective therapies for enhancing the efficacy of radiotherapy, particularly in the context of tumors that are resistant to radiotherapy. To address this need, the presently disclosed subject matter provides inter alia methods for increasing the radiosensitivity of a cell or tissue. Such methods can be useful for enhancing the efficacy of anti-proliferative treatments such as, but not limited to chemotherapy and radiotherapy, among other applications.